Börjeson -Forssman -Lehmann syndrome: A case report / 中南大学学报(医学版)

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked intellectual disability. The main features of the patients include intellectual disability/global developmental delay, characteristic face, anomalies of fingers and toes, hypogonadism, linear skin hyperpigmentation, and tooth abnormalities in female patients, and obesity in male patients. A case of BFLS caused by a novel mutation of PHF6 gene who was treated in the Department of Pediatrics, Xiangya Hospital, Central South University was reported. The 11 months old girl presented the following symptons: Global developmental delay, characteristic face, sparse hair, ocular hypertelorism, flat nasal bridge, hairy anterior to the tragus, thin upper lip, dental anomalies, ankyloglossia, simian line, tapering fingers, camptodactylia, and linear skin hyperpigmentation. The gene results of the second-generation sequencing technology showed that there was a novel heterozygous mutation site c.346C>T (p.Arg116*) of the PHF6 (NM032458.3), variation rating as pathogenic variation. During the follow-up, the patient developed astigmatism, strabismus, awake bruxism, and stereotyped behavior, and the linear skin hyperpigmentation became gradually more evident. The disease is lack of effective therapy so far.

NEXMIF mutations in intellectual disability and epilepsy: A report of 2 cases and literature review / 中南大学学报(医学版)

More than 100 genes located on the X chromosome have been found to be associated with X-linked intellectual disability (XLID) to date, and NEXMIF is a pathogenic gene for XLID. In addition to intellectual disability, patients with NEXMIF gene mutation can also have other neurological symptoms, such as epilepsy, abnormal behavior, and hypotonia, as well as abnormalities of other systems. Two children with intellectual disability and epilepsy caused by NEXMIF gene mutation were treated in the Department of Pediatrics, Xiangya Hospital, Central South University from March 8, 2017 to June 20, 2020. Patient 1, a 7 years and 8 months old girl, visited our department because of the delayed psychomotor development. Physical examination revealed strabismus (right eye), hyperactivity, and loss of concentration. Intelligence test showed a developmental quotient of 43.6. Electroencephalogram showed abnormal discharge, and cranial imaging appeared normal. Whole exome sequencing revealed a de novo heterozygous mutation, c.2189delC (p.S730Lfs*17) in the NEXMIF gene (NM_001008537). During the follow-up period, the patient developed epileptic seizures, mainly manifested as generalized and absent seizures. She took the medicine of levetiracetam and lamotrigine, and the seizures were under control. Patient 2, a 6-months old boy, visited our department due to developmental regression and seizures. He showed poor reactions to light and sound, and was not able to raise head without aid. Hypotonia was also noticed. The electroencephalogram showed intermittent hyperarrhythmia, and spasms were monitored. He was given topiramate and adrenocorticotrophic hormone (ACTH). Whole exome sequencing detected a de novo c.592C>T (Q198X) mutation in NEXMIF gene. During the follow-up period, the seizures were reduced with vigabatrin. He had no obvious progress in the psychomotor development, and presented strabismus. There were 91 cases reported abroad, 1 case reported in China, and 2 patients were included in this study. A total of 85 variants in NEXMIF gene were found, involving 83 variants reported in PubMed and HGMD, and the 2 new variants presented in our patients. The patients with variants in NEXMIF gene all had mild to severe intellectual disability. Behavioral abnormalities, epilepsy, hypotonia, and other neurological symptoms are frequently presented. The phenotype of male partially overlaps with that of female. Male patients often have more severe intellectual disability, impaired language, and autistic features, while female patients often have refractory epilepsy. Most of the variants reported so far were loss-of-function resulted in the reduced protein expression of NEXMIF. The degree of NEXMIF loss appears to correlate with the severity of the phenotype.

Cardio / 中南大学学报(医学版)

Cardio-facio-cutaneous (CFC) syndrome is an extremely rare autosomal dominant genetic disease due to BRAF and other gene mutations. The main characteristics of the patients are craniofacial deformities, cardiac malformations, skin abnormalities, delay of language and motor development, gastrointestinal dysfunction, intellectual disability, and epilepsy. In this case, the child has a typical CFC syndrome face and developmental delay. The gene results of the second-generation sequencing technology showed that there was a mutation site c.1741A>G (p. Asn581Asp) (heterozygous) in exon 14 of the BRAF (NM_004333.5) gene. The mutation was not observed in the child's parents. The above-mentioned mutation may be a de novo mutation. There is no effective therapy for this disease so far.

Application of ventricular shunt for children with post-infective hydrocephalus / 中南大学学报(医学版)

To investigate the effects of ventricular shunt placement in children with post-infective hydrocephalus.
 Methods: A total of 24 cases of post-infectious hydrocephalus, who received ventricular shunt, were enrolled. Age, gender, disease progression, clinical manifestation, laboratory data, treatment, prognosis, complication, and sequela for each patient were retrospectively reviewed.
 Results: Of the 24 cases, 8 had a full recovery, 11 had slight sequela, 2 had severe sequela, 1 was in vegetative state, and 2 died because of bacterial meningitis and tubercular meningitis. Epilepsy, mental impairment, visual and hearing damage were the main sequelae.
 Conclusion: Ventricular shunt is the preferred treatment in children with post-infective hydrocephalus, which shows positive clinical efficacy and can improve the long-term prognosis of such patients.

A case of Okur-Chung syndrome caused by CSNK2A1 gene variation and review of literature / 中华儿科杂志

Objective@#To summarize the clinical features and gene variation characteristics of a child with Okur-Chung syndrome caused by CSNK2A1 gene variation.@*Methods@#The medical records of one patient who was diagnosed with Okur-Chung syndrome in Department of Pediatrics, Xiangya Hospital of Central South University in July 2018 were analyzed. Using "CSNK2A1" gene as the keyword, relevant information about CSNK2A1 gene was searched at CNKI, Wangfang Data, OMIM, PubMed, ClinVar, Decipher (until August 2018). The characteristics of CSNK2A1 gene variation and the clinical phenotype of children with Okur-Chung syndrome were summarized.@*Results@#The boy, 1 year and 8 months old, was sent to hospital at the age of 1 year and 6 months because of delayed growth for more than 1 year. He was susceptible to cough while eating or drinking. He was also suffering from constipation and poor sleep. Physical examination showed that his body weight was 10.2 kg, microcephalus, broad nasal bridge, micrognathia and hypotonia were observed. Whole exome-sequencing test identified a de novo heterozygous variation c.524A>G (p.D175G) in CSNK2A1 gene. This was the first case report of CSNK2A1 gene variation in the mainland of China. So far, a total of 52 cases were reported worldwide (52 single nucleotide variants), including 35 cases in 7 articles, 9 cases in Decipher database and 14 cases in ClinVar database, 6 of which were also reported in PubMed. In previously reported 52 cases, there were 48 missense variants, whereas, splice and frameshift variations were found in 3 cases and 1 case, respectively. Among the variation sites, p.K198R was the most common sites (12 cases), followed by p.R47 (6 cases), p.R80H (4 cases) and p.S51 (4 cases). Among these 52 cases, only 27 cases have been elaborately described in other studies, so the clinical characteristics were summarized in 28 cases eventually (including 27 cases in the articles and this patient), 27 of whom presented severe intellectual disability or global development delay, 1 case with mild language development delay, and 19 had hypotonia; 8 had autism spectrum disorders, 5 had attention deficit hyperactivity disorder, and 9 had sleep problems. 20 had dysmorphic facial features, 10 of them had microcephalus. 16 had failure to thrive or short stature, 12 had gastrointestinal or oromotor problem, 5 had immunological problem, and 4 had skin abnormalities.@*Conclusions@#The main clinical feature of patients with CSNK2A1 gene variations is intellectual disability with multiple systems involved, such as microcephalus, abnormal facial shape and hypotonia. The variation of CSNK2A1 gene is the cause of Okur-Chung syndrome. Missense variation is the main cause, and P. K198R is the hotspot variation.

Socio-cultural factors of global developmental delay children / 中国医师杂志

Objective To summarize the clinical features of global developmental delay (GDD) children,and to explore the relationship between severity of GDD and social-culture factors.Methods Sign the informed consent before enrollment.Collect clinical data in detail about 100 GDD children (GDD group) and 95 children with normal development (healthy control group),and analyze their regular clinical data,physical examination,intellectual disability test,electroencephalography (EEG) and cranial imaging test.Spearman rank correlation was used to analyze the differences of social and cultural factors between GDD group and healthy control group,such as maternal reproductive age,parental education level and family economic status.At the same time,we compared the lag degree of total developmental quotient and the degree of developmental retardation of five energy areas with the above factors.Results Significant associations were found between GDD and maternal/paternal education,economic level of family,but no sgnificant association was found between maternal age and GDD.And analysis in the relationship between severity of delay in all domains of the child's developmental status about language and social-culture factors,we only obtained the severity of delay in abilities about language is related with maternal education.Spearman rank correlation statistics explains that if there are the lower level of education with mothers,the delay of language domain will more severe (rs =-0.505,P ＜ 0.05).Conclusions Significant associations were found between GDD and maternal/paternal education,economic level of family.The higher maternal education was an important protective factor against risk of GDD.Improving the cognition of parents in child health care,early be diagnosed,early be intervened,is the most important for children with language development.

The clinical characteristics and molecular genetics of infantile neuroaxonal dystrophy: The current research progress / 中国医师杂志

Infantile neuroaxonal dystrophy (INAD) is a rare autosome-recessive disease characterized by progressive motor and cognitive regression.The PLA2G6 gene is its causative gene,which encodes calcium-independent phospholipase A2 enzyme (iPLA2-VIA).The diagnosis of INAD is difficult because of its clinical heterogeneity,and the rate of misdiagnosis is high.The purpose of this study is to describe the clinical characteristics,molecular genetics,treatment and prognosis of INAD to improve the acknowledgement of INAD in medical workers and to help make an early diagnosis of INAD.

Clinical features and genetic analysis of intellectual disability in children with epilepsy of unknown causes / 中华实用儿科临床杂志

Objective To explore the clinical features,genetic causes and prognosis of intellectual disability with epilepsy(ID-E)in children.Methods The data of unknown causes of ID-E children(n=40)who were identified in Department of Pediatrics,Xiangya Hospital of Central South University from March 2015 to March 2016 were respectively analyzed,and follow-up studies were performed to investigate the epilepsy control and intellectual deve-lopment.Results Forty unexplained ID-E included 25(62.5％)male,and 34(85.0％)cases were severe intellectual disability patients.The onset age of epilepsy was 0.16 to 8.00 years old,median age was 1.5 years old.Twenty cases(50.0％)had slow electroencephalogram background,and 22 cases(55.0％)had focal spikes.Ten cases(25.0％)had abnormal cranial images,with brain dysplasia or atrophy.Follow-up lasted from 0.58 to 1.58 years,and 19 cases(47.5％)had seizure control.Twenty-five cases(62.5％)had used at least 2 anti-epilepsy drugs during follow-up,and 19 cases(47.5％)had drug refractory epilepsy.Improvement of mental or motor development in epilepsy controlled group and the uncontrolled group were 12 cases(63.2％)and 2 cases(9.5％).There were separately 8 cases(8/40 cases,20.0％)and 3 cases(3/16 cases,18.8％)diagnosed respectively by whole genome-wide analysis of copy number variants(CNVs)and gene-panel whose CNVs test findings were negative.Conclusions ID-E patients of unknown causes have the following clinical features:they were mostly found in male patients with severe intellectual disability,and drug refractory epilepsy patients have rather high percentage;well controlling of epilepsy is useful for improvement of mental and motor development.Genetic analysis is significant for control and prognosis of ID-E patients,and genome-wide CNVs have high positive rates which can be used as first-tier test to detect genetic etiology of ID-E of unknown cause.